Blinatumomab (Blincyto)

Number: 0891

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses blinatumomab (Blincyto) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

1. Criteria for Initial Approval

   B-cell Precursor Acute Lymphoblastic Leukemia

   Aetna considers blinatumomab (Blincyto) medically necessary for treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) when one of the following criteria are met:

   1. The requested medication will be used as consolidation or maintenance therapy; or
   2. The requested medication will be used for relapsed or refractory disease.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections)

2. Continuation of Therapy

   Aetna considers continuation of blinatumomab (Blincyto) therapy medically necessary in members for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Blinatumomab (Blincyto) is available as 35 mcg of lyophilized powder in a single-dose vial for reconstitution for intravenous infusion.  

B-cell Acute Lymphoblastic Leukemia

Blinatumomab (Blincyto) is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. The labeling states that it is important to strictly follow instructions for preparation (including admixing) and administration to prevent overdose and underdose. Premedicate with prednisone or equivalent dexamethasone. See Full Prescribing Information for recommended dose by patient weight and schedule. Patients greater than or equal to 45 kg receive a fixed-dose. For patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA).

For the treatment of Relapsed or Refractory B-cell Precursor ALL, the labeling for Blincyto recommends hospitalization for the first 9 days of the first cycle and the first 2 days of the second cycle. A treatment course consists of up to 2 cycles of Blincyto for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy. A single cycle of treatment of Blincyto induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). A single cycle of treatment of Blincyto continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days). 

For the treatment of MRD-positive B-cell Precursor ALL, the labeling for Blincyto recommends hospitalization for the first 3 days of the first cycle and the first 2 days of the second cycle. A treatment course consists of 1 cycle of Blincyto for induction followed by up to 3 additional cycles for consolidation. A single cycle of treatment of Blincyto induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).

Source:  Amgen, 2023

Experimental and Investigational

Aetna considers blinatumomab experimental and investigational for all other indications including the following (not an all-inclusive list):

• Acute myeloid leukemia
• HLA loss relapse after hematopoietic stem cell transplantation
• Melanoma
• Non-Hodgkin's lymphoma (e.g., Burkitt lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma)
• Solid tumors.

Aetna considers combined blinatumomab and tyrosine kinase inhibitor for the treatment of relapsed Philadelphia chromosome-positive leukemia experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers combined blinatumomab and donor lymphocyte infusion for the treatment of mixed-phenotype acute leukemia experimental and investigational because the effectiveness of this approach has not been established.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Blinatumomab (Blincyto) :
Other CPT codes related to the CPB:
38242	Allogeneic lymphocyte infusions
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9039	Injection, blinatumomab, 1 mcg
ICD-10 codes covered if selection criteria are met:
C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.01	Acute lymphoblastic leukemia, in remission
C91.02	Acute lymphoblastic leukemia, in relapse
ICD-10 codes not covered for indications listed in the CPB:
C00.0 - C90.02, C90.20 - C90.32, C96.0 - D09.9	Malignant solid tumors
C92.90 - C92.92	Myeloid leukemia, unspecified [acute]
C95.00 - C95.02	Acute leukemia of unspecified cell type

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Blincyto is indicated for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults and pediatric patients.
• Blincyto is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adults and pediatric patients.

Compendial Uses

• Acute lymphoblastic leukemia (ALL)

Blinatumomab is available as Blincyto (Amgen Inc.) and is a bispecific CD19-directed CD3 T-cell engager. Blincyto (blinatumomab) binds to CD19 expressed on the surface of cells of B‐lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blincyto (blinatumomab) mediates the formation of a synapse between the T cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+ cells (Amgen, 2021).

Per the prescribing information, blinatumomab (Blincyto) carries the following warnings and precautions:

• Cytokine release syndrome (CRS): CRS. which may be life-threatening or fatal, was noted in 15% of patients with relapsed ALL and in 7% of patients with MRD-positive ALL receiving Blincyto in clinical trials.
• Neurological toxicities: In patients receiving Blincyto in clinical studies, neurological toxicities were note in approximately 65% of patients.
• Infections: In patients receiving Blincyto in clinical studies, serious infections, including sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were noted in approximately 25% of patients, some of which were life-threatening or fatal.
• Tumor lysis syndrome
• Neutropenia and febrile neutropenia
• Effects on ability to drive and use machines
• Elevated liver enzymes
• Pancreatitis
• Leukoencephalopathy
• Preparation and administration errors
• Immunization
• Risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative.

Per the prescribing information, the most common adverse reactions (≥ 20%) were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia.

B-cell Precursor Acute Lymphoblastic Leukemia (ALL)

The U.S. Food and Drug Administration (FDA) approved blinatumomab (Blincyto) (Amgen, Thousand Oaks, CA) to treat patients with relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia (B-cell ALL) (FDA, 2014). This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

The FDA granted Blincyto breakthrough therapy designation, priority review and orphan product designation because the sponsor demonstrated through preliminary clinical evidence that the drug may offer a substantial improvement over available therapies; the drug had the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and the drug is intended to treat a rare disease, respectively (FDA, 2014).  

The FDA approval of Blincyto was based on results of Amgen's '211 trial, a phase 2, multicenter, single-arm open-label study involving 185 adults with Philadelphia chromosome-negative relapsed or refractory precursor B-cell ALL (Amgen, 2014).  Eligible patients were greater than 18 years of age with Ph- relapsed or refractory B-cell precursor ALL.  Relapsed or refractory was defined as relapsed with first remission duration of less than 12 months in the first salvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and had greater than 10 % blasts in bone marrow.  All participants were treated with blinatumomab for at least 4 weeks via infusion.  Of the 185 patients evaluated in the trial, 41.6 % (77/185; 95 % confidence interval [CI]: 34.4 to 49.1) achieved complete remission or complete remission with partial hematologic recovery (CR/CRh*) within 2 cycles of treatment with blinatumomab, which was the primary end-point of the study.  The majority of responses (81 % [62/77]) occurred within the first cycle of treatment.  Among patients who achieved CR/CRh*, 39 % (30/77) went on to HSCT, and 75.3 % (58/77 95 %CI: 64.2 to 84.4) achieved minimal residual disease (MRD) response. 

Studies used to assess effectiveness of Blincyto (blinatumomab) defined relapsed or refractory as: relapsed with first remission duration of ≤ 12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation [HSCT], and had ≥ 10% blasts in bone marrow.

Blincyto was approved under the FDA’s accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients (FDA, 2014).  The FDA is requiring the manufacturer to conduct a study to verify that the drug improves survival in participants with relapsed or refractory Philadelphia-negative precursor B-cell ALL. 

Blincyto carries a boxed warning that some clinical trial participants had problems with cytokine release syndrome (CRS), or neurological toxicities which may be life threatening or fatal (FDA, 2014).  The labeling recommends that blinatumomab be interrupted or discontinued in patients experiencing these side effects.

The most common adverse reactions (greater than or equal to 20 %) were pyrexia (62 %), headache (36 %), peripheral edema (25 %), febrile neutropenia (25 %), nausea (25 %), hypokalaemia (23 %), rash (21 %), tremor (20 %) and constipation (20 %) (Amgen, 2014).  Serious adverse reactions were reported in 65 % of patients.  The most common serious adverse reactions (greaterthan or equal to 2 %) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia and headache.

Life-threatening or fatal CRS occurred in patients receiving blinatumomab (Amgen, 2014).  The labeling states that manifestations of CRS may be indistinguishable from Infusion reactions.  The labeling states that patients should be closely monitored for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).  The labeling recommends that blinatumomab be interrupted or discontinued if CRS occurs. 

Approximately 50 % of patients receiving blinatumomab in clinical trials experienced neurological toxicities (Amgen, 2014).  Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15 % of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders.  The median time to onset of any neurological toxicity was 7 days.  The labeling recommends monitoring patients for signs or symptoms and recommends interrupting or discontinuing blinatumomab if these occur. 

Approximately 25 % of patients receiving blinatumomab experienced serious infections, some of which were life-threatening or fatal (Amgen, 2014).  The labeling recommends administration of prophylactic antibiotics surveillance testing as appropriate during treatment.  The labeling states that patients should be monitored for signs or symptoms of infection and treated appropriately, including interruption or discontinuation of blinatumomab as needed.

Life-threatening or fatal tumor lysis syndrome (TLS) has been observed with blinatumomab (Amgen, 2014).  The labeling recommends use of preventive measures, including pre-treatment non-toxic cytoreduction and on treatment hydration, during blinatumomab treatment.  Patients should be monitored for signs and symptoms of TLS and blinatumomab interrupted or discontinued as needed to manage these events.

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed with blinatumomab  (Amgen, 2014).  Appropriate laboratory parameters should be monitored during blinatumomab infusion and blinatumomab should be interrupted if prolonged neutropenia occurs.

Due to the possibility of neurological events, including seizures, patients receiving blinatumomab are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while blinatumomab is being administered (Amgen, 2014).

Transient elevations in liver enzymes have been associated with blinatumomab treatment (Amgen, 2014).  The majority of these events were observed in the setting of CRS.  The median time to onset was 15 days.  Grade 3 or greater elevations in liver enzymes occurred in 6 % of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1 % of patients. ALT, AST, gamma-glutamyl transferase (GGT), and TBILI should be monitored prior to the start of and during blinatumomab treatment.  The labeling states that blinatumomab treatment should be interrupted if transaminases rise to greater than 5 times the upper limit of normal (ULN) or if TBILI rises to greater than 3 times ULN.

Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving blinatumomab, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy (Amgen, 2014).

Blinatumomab is contraindicated to patients with known hypersensitivity to blinatumomab or to any component of the product formulation (Amgen, 2014).  The labeling of Blincyto recommends that patients be monitored for signs and symptoms of infection and treated appropriately.  The labeling states that patients should be advised to refrain from driving and engaging in hazardous occupations or activities such as driving, operating heavy or potentially dangerous machinery while blinatumomab is being administered.

The FDA approved Blincyto with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a communication plan to inform health care providers about the serious risks and the potential for preparation and administration errors (FDA, 2014).

Acute Myeloid Leukemia

Sasine and Schiller (2015) noted that high-risk acute myeloid leukemia (AML) is defined by clinical and biologic features that predict for poor response to induction chemotherapy and high risk of relapse.  Despite even the most aggressive and well-developed strategies for care, most patients succumb to the disease.  No currently available treatment has demonstrated consistent efficacy in terms of remission induction or long-term survival.  These researchers highlighted some of the emerging strategies to treat high-risk AML with an emphasis on clinical trials of novel strategies currently enrolling patients.  Targeted molecular therapies, novel cytotoxics, and immune-based therapies are under investigation for the management of high-risk AML.  Some of the agents covered include TKIs targeted to AML specific oncoproteins, nanoparticle formulations of existing drugs, nucleoside analogs, monoclonal antibodies, chimeric antigen receptors, bi-specific T-cell engaging antibodies, and vaccines.  As the understanding of the biology of AML has improved, targeted therapy for AML has emerged, offering to change not only response rate, but also the nature of response.  Differentiation, rather than necrosis or apoptosis, is often seen in response to targeted agents and may be seen more frequently in the future.  Interventions that might be more widely used in the near future include FLT3 inhibitors and nanoparticle formulations of drugs already known to have activity in the disease.  Long term immune therapy holds significant promise.

Combination Therapy with Blinatumomab 

Assi and colleagues (2017) noted that the treatment of Philadelphia chromosome-positive (Ph+) ALL has been revolutionized with the introduction of TKIs and the combination of these agents with chemotherapy.  Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody with clinical activity as single-agent in the relapsed setting and independent of BCR-ABL1 mutational status, including T315I.  The combination of blinatumomab with a TKI may further improve outcomes for this high-risk population, including higher eradication of MRD and minimize the use of chemotherapy.  These investigators retrospectively studied 12 adults with relapsed/refractory Ph+ ALL (n = 9) and chronic myeloid leukemia (CML) in blast crisis (n = 3), treated with the combination blinatumomab and a TKI (ponatinib, n = 8; dasatinib, n = 3; bosutinib, n = 1).  All patients have previously failed at least 1 line of chemotherapy, including allogeneic stem cell transplantation (ASCT), and 1 class of TKIs.  Patients were treated for either overt hematologic relapse (n = 6) or persistent MRD following other regimens (n = 6).  The complete hematologic, cytogenetic, and molecular response rates were 50 % (3/6), 71 % (5/7), and 75 % (9/12), respectively; 2 cases of grade 2 CRS were observed, all of which resolved with steroids and tocilizumab.  No cardiovascular AEs were encountered.  With a median follow-up of 8 months, the median survival was not reached; the 6-month and 1-year overall survival (OS) rates were 73 %.  The authors concluded that the combination of blinatumomab with TKI was safe and effective in patients with relapsed/refractory Ph+ disease.; prospective studies are needed.

Durer and colleagues (2019) stated that blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission.  These researchers presented the case of a 51-year old woman with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation (TBI)-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen (HLA)-matched (10/10) donor and achieved complete remission (CR) with MRD negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI.  The authors concluded that to the best of their knowledge, this was the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Choi and colleagues (2020) noted that the therapeutic approach for r/r ALL remains to be a challenge.  In this single-case study, the patient was diagnosed with B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic HSCT (one after first CR [CR1] and the other after CR2).  During blinatumomab monotherapy, he developed an extra-medullary relapse.  Finally, the combined therapy with clofarabine, DLI, and blinatumomab induced CR of the bone marrow and extra-medullary relapse.  Unfortunately, the patient developed CNS relapse, however, this case showed a promising potential for combination therapy with clofarabine, DLI, and blinatumomab in r/r B-cell ALL.

HLA Loss Relapse After Hematopoietic Stem Cell Transplantation

Wu and colleagues (2021) noted that loss of patient-specific HLA after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered as a relapse mechanism for lacking the incompatible molecule to elicit allo-reactivity, which extensively diminishing graft-versus-leukemia (GVL) effects. Blinatumomab could yield a profound response via re-directing T cells towards malignant lymphoblasts in B-ALL. These researchers examined the feasibility of blinatumomab in treating patients with HLA loss relapse following haplo-HSCT. A total of 4 eligible patients undergoing HLA loss relapse following haplo-HSCT were enrolled in the study. They achieved a CR/CR with partial hematologic recovery (CR/CRh) with 3 MRD-negative response within the 1st cycle of treatment; 3 of the 4 subjects met a primary endpoint with CR/CRh and MRD-negative response within 2 cycles of treatment. One patient developed new extra-medullary sites of skin after the 1st cycle; and CRS was observed in 1 patient. Cytopenias, as well as elevated alanine aminotransferase and aspartate aminotransferase, were 2 common adverse effects during treatment. The authors concluded that the early detection of patient-specific HLA loss on leukemic cells is of the great importance of selecting salvage treatment and this study was the first to report the clinical efficacy of blinatumomab in HLA loss occurrence. Blinatumomab could re-direct allogeneic T cells to leukemic cells, restoring GVL effects in patients of HLA loss relapse following allo-HSCT. It could exert quick resolution with controllable AEs. These researchers stated that further randomized clinical trials examining the effects of blinatumomab in patients with HLA loss relapse after HSCT is needed.

Melanoma

Neubauer (2017) noted that the newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research.  The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic.  Ipilimumab was the first MAb developed against a target present on T cells after becoming activated, CTLA-4.  In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide . However, the therapy with this antibody harbors significant toxicity.  Meanwhile, other targets such as PD-1, also expressed on (late) activated T cells, were identified, and therapies with antibodies inhibiting PD-1/PD-L1 are less toxic.  Although these antibodies show response only in a minority of patients, the benefit appeared durable in some of these patients.  In solid tumors such as melanoma or non-small cell lung cancer (NSCLC), treatment with PD-1 inhibitors has resulted in a significant prolongation of survival, even in first-line treatment.  As these drugs have been approved for many indications, it is important to know the drugs and side effects.   Resistance towards these drugs are caused by low expression of the natural ligand, PD-L1, in the tumor tissue, as well as acquired loss of signal transduction of interferon-related genes such as JAK1 or JAK2, respectively.  Also new in cancer therapy are BiTEs such as blinatumomab, and autologous chimeric antigen receptor-modified T cells (CAR-Ts).

Non-Hodgkin’s Lymphomas (e.g., Burkitt Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma)

Oak and Bartlett (2015) stated that blinatumomab is a bi-specific T-cell engager (BiTE) molecule that recruits cytotoxic T cells to target tumor B cells by linking the CD3 and CD19 antigens.  Among the various formats of bi-specific antibodies developed in the past 50 years, the BiTE class is remarkable for its low effector-to-target ratio, high tissue penetration and singular ability to activate T cells independent of MHC class I presentation or co-stimulation.  Blinatumomab has been studied in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) and B-precursor acute lymphoblastic leukemia (B-ALL).  These researchers reviewed the current literature on blinatumomab including its pharmacology, pre-clinical findings, clinical trials in B-cell NHL; and to a lesser extent, phase II studies in B-ALL.  These investigators discussed the potential future directions in light of other new competing therapies for NHL and unmet clinical needs in the market.  The authors concluded that the recent approval of blinatumomab for B-ALL symbolizes a breakthrough for BiTE technology with prospective application in the targeted therapy of other cancers.  They stated that although blinatumomab seems an unlikely option for treating indolent lymphoma due to toxicity, the need for long-term continuous infusion therapy and multiple promising well-tolerated oral agents, it holds promise for aggressive NHL patients whose diseases are refractory to current standard approaches.  They stated that larger trials are needed to demonstrate blinatumomab's curative potential in aggressive histologies.

Dozzo and associates (2016) noted that Burkitt lymphoma (BL) is an aggressive B-cell neoplasm displaying highly characteristic clinico-diagnostic features, the biologic hallmark of which is a translocation involving immunoglobulin and c-MYC genes.  It presents as sporadic, endemic, or epidemic disease.  Endemicity is pathogenetically linked to an imbalance of the immune system that occurs in African children infected by malaria parasites and Epstein-Barr virus (EBV), while the epidemic form strictly follows the pattern of infection by HIV.  These investigators stated that approximately 50 % of all BL patients are younger than 40 years, and 1/3 belong to the adolescent and young adult (AYA) subset, defined by an age between 15 and 25 to 40 years, based on selection criteria used in different reports.  Burkitt lymphoma shows propensity to extra-nodal involvement of abdominal organs, bone marrow, and central nervous system (CNS), and can cause severe metabolic and renal impairment.  Nevertheless, BL is highly responsive to specifically designed short-intensive, rotational multi-agent chemotherapy programs, empowered by the anti-CD20 monoclonal antibody (MAb) rituximab.  When carefully applied with appropriate supportive measures, these modern programs achieved a cure rate of approximately 90 % in the average AYA patient, irrespective of clinical stage, which is the best result achievable in any aggressive lymphoid malignancy to-date.  The challenges ahead concern the following: optimization of management in under-developed countries, with reduction of diagnostic and referral-for-care intervals, and the applicability of currently curative regimens; the development of lower intensity but equally effective treatments for frail or immunocompromised patients at risk of death by complications; the identification of very high-risk patients through positron-emission tomography (PET) and MRD assays; and the assessment in these and the few refractory/relapsed (r/r) ones of new MAbs (e.g., ofatumumab, blinatumomab, inotuzumab ozogamicin) and new molecules targeting c-MYC and key proliferative steps of B-cell malignancies.

Viardot and colleagues (2016) stated that few patients with r/r diffuse large B-cell lymphoma (DLBCL) attained prolonged disease-free survival (DFS).  In a phase II clinical trial, these researchers evaluated step-wise (9 to 28 to 112 μg/day with weekly dose increases; n = 23) or flat (112 μg/day; n = 2) dosing of blinatumomab by continuous infusion, with dexamethasone prophylaxis, in patients with r/r DLBCL.  Patients received a median of 3 prior lines of therapy.  Median time since last regimen was 1.5 months; 17 patients ended treatment in cycle 1 (induction), 7 in cycle 2 (consolidation), and 1 in re-treatment.  Among 21 evaluable patients, the overall response rate (ORR) after 1 blinatumomab cycle was 43 %, including CRs in 19 %; 3 patients had late CR in follow-up without other treatment.  The most common adverse events (AEs) with step-wise dosing were tremor (48 %), pyrexia (44 %), fatigue (26 %), and edema (26 %).  Grade 3 neurologic events with step-wise dosing were encephalopathy and aphasia (each 9 %) and tremor, speech disorder, dizziness, somnolence, and disorientation (each 4 %).  Of 5 (22 %) patients who discontinued step-wise dosing because of AEs, 4 (17 %) had neurologic events; most neurologic events resolved.  The flat-dose cohort was stopped because of grade 3 neurologic events in both patients.  The authors concluded that blinatumomab monotherapy appeared effective in patients with r/r DLBCL, a heavily pre-treated patient population with a high unmet medical need.  Moreover, they stated that future strategies for blinatumomab therapy to optimize the balance of efficacy and tolerability in r/r DLBCL may include modified dose schedules that provide the target dose earlier in the course of therapy, a better understanding of minimum treatment duration necessary to achieve responses, or using blinatumomab as consolidation therapy after initial "debulking".

Anastasia and Rossi (2016) noted that follicular lymphoma(FL) is the most common indolent NHL and constitutes 15 % to 30 % of lymphoma diagnoses.  The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10 years.  The impossibility of achieving a definite cure, have prompted investigations into the possible role of more active and less toxic strategies with innovative therapeutic agents.  Recently research demonstrated that approximately 20 % of patients with FL relapse within 2 years after achieving remission with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and have a poor prognosis.  It is conceivable that this particularly chemo-resistant population would benefit from specifically targeting the biologic and genetic factors that likely contribute to their poor prognosis.  Evolving strategies for difficult to treat FL patients have recently considered immunomodulatory agents, new MAbs as well as drugs targeting selective intra-cellular pathways.  The importance of targeting the micro-environment together with the malignant FL cell has been particularly underscored.  These investigators reviewed the most promising approaches, such as combining anti-CD20 antibodies with immunomodulatory drugs (lenalidomide), MAbs directed against other surface antigens such as CD22 and CD23 (epratuzumab, lumiliximab), immunomodulatory antibodies such as PD-1, or inhibitors of key steps in the B-cell receptor pathway signaling such as PI3K inhibitors (idelalisib, duvelisib).  Another highly attractive approach is the application of the BiTE antibody blinatumomab that targets both CD19 and CD3 antigens.  The authors highlighted the potential of these therapies, taking into account their toxicity; results of phase III trials are awaited to confirm the benefit of these new therapeutic strategies toward a new era of chemotherapy-free treatment for FL.

Bukhari and Lee (2019) stated that blinatumomab is a member of a novel class of bi-specific antibody constructs with dual binding specificities.  While its primary clinical use has been in B-cell ALL, its role in the treatment of B-cell NHL (B-NHL) is less well established.  These investigators provided a brief overview of the market, unmet needs, and how blinatumomab fits in to the evolving armamentarium of lymphoma-directed therapies.  They addressed its therapeutic role in salvage therapy for r/r NHL, as consolidation for high-risk DLBCL following ASCT, and through various combinations with other available agents.  Moreover, these researchers highlighted key competitors.  The authors concluded that although blinatumomab showed impressive results in phase-I and phase-II clinical trials for r/r DLBCL, its future utility remains to be seen in this clinical setting due to lack of phase-III clinical trial and FDA approval of CD19 CART therapy.  A new CD19/CD3 and several CD20/CD3 bi-specific antibodies with longer half-life and resultant easier mode of administration that can overcome the major barriers of its use in clinical practice are in the pipeline and their role in NHL treatment are actively examined.

In an open-label, phase-II clinical trial, Coyle and colleagues (2020) examined the safety and efficacy of blinatumomab as second salvage for aggressive r/r B-NHL following platinum-based first salvage chemotherapy.  A total of 41 patients with aggressive disease (32 % relapsed; 68 % refractory) enrolled and received step-wise blinatumomab (9-28-112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46 %) completed cycle 1 and 3 (7 %) completed cycle 2 . The ORR after 12 weeks was 37 %, including 9 (22 %) complete metabolic responses; 8 (20 %) patients (all responders) subsequently received HSCTs.  Grade greater than or equal to 3 AEs were reported in 29 (71 %) patients.  Grade-3 CRS occurred in 1 patient.  Grade-3 neurologic events occurred in 10 (24 %) patients; all resolved.  The authors concluded that blinatumomab monotherapy appeared effective as second salvage therapy in patients with r/r aggressive B-NHL.  These researchers stated that these findings implied a potential for effective use of blinatumomab earlier in the salvage treatment continuum and raise the question of whether efficacy could be improved in combination with other conventional or experimental therapies; however, additional investigation is needed.

The authors concluded that this study was limited by a relatively high rate of treatment discontinuation during the first treatment cycle, primarily due to disease progression (n = 17) rather than to AEs (n = 4).  Overall, 46 % of patients completed cycle 1 and 7 % completed the optional cycle 2.  Consequently, exposure to blinatumomab was lower than anticipated, with 34 % of patients receiving less than 50 % of the intended dose, and only 59 % receiving greater than or equal to 80 % of the intended dose.  Although at least 1 week of treatment at the target dose of 112 μg/day appeared necessary for efficacy examining other dosing strategies may be appropriate.  Despite this limitation, the ORR and complete metabolic response (CMR) rates observed with blinatumomab were encouraging given the aggressive nature of heavily pretreated r/r disease in this population of patients.  The longer follow-up period at the final analysis will allow for better estimation of the effects of blinatumomab on OS and relapse-free survival (RFS) in this cohort.

Nagele and colleagues (2021) noted that blinatumomab is a first-in-class immunotherapy based on the bispecific T-cell engager (BiTE) immune-oncology platform, which redirects CD3+ T cells to kill CD19+ target cells.  In an exploratory study, these investigators described the correlation between B- and T-cell kinetics and response to blinatumomab in patients with relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL).  The clinical efficacy of treatment with blinatumomab in patients with r/r NHL was recently examined in a dose-escalation and expansion, phase-I clinical trial wherein 76 patients received blinatumomab by continuous intravenous infusion at various doses (0.5 to 90 μg/m2/day).  B-Cell depletion and expansion of CD3+, CD4+, and CD8+ T cells was analyzed in patients stratified per clinical response (CR, n = 16; partial response [PR], stable disease [SD], or progressive disease [PD], n = 54) for at least 4 weeks (additional 4 weeks after clinical benefit) from the date of administration of blinatumomab until dose-limiting toxicity (DLT) or PD.  B-cell depletion kinetics were faster in patients who had a CR than in patients who did not have a CR (PR, SD, or PD).  T-cell expansion (T-cell counts exceeding the baseline level on day 22) was more pronounced in patients with CR than in patients without CR.  T-cell expansion in patients with CR correlated with increased T-cell counts of both CD4+ and CD8+ T cells compared with patients without CR.  Patients with r/r NHL who achieved a CR had faster B-cell depletion and increased expansion of CD3+, CD4+, and CD8+ T cells than patients who did not achieve a CR.

The authors stated that a drawback of this exploratory study was the smaller number of patients who achieved a CR (n = 16) compared with those who did not achieve a CR (n = 55).  Statistical analysis could not be carried out because of the limited number of patients.  Inter-patient variability could also influence the interpretation of the results. However, data indicated that patients who received greater than or equal to 60 µg/m2/day blinatumomab had greater B-cell depletion, increased T-cell expansion, and better response compared with patients who received less than or equal to 30 µg/m2/day blinatumomab.  Nevertheless, the results of this study may lead to the assumption that increasing the B-cell depletion within the first days after treatment start, probably by increasing the starting dose of blinatumomab, could be beneficial for the clinical response of patients with r/r NHL.  However, larger patient numbers would be needed to examine if increasing the B-cell depletion in the first days after treatment start in patients with r/r NHL would significantly correlate with a better response.

Bohler et al (2022) stated that in patients with relapsed/refractory Burkitt lymphoma (r/r BL), OS is poor, and effective therapies and evidence for the best therapy are lacking; blinatumomab may represent a novel option.  However, only limited data on the use of blinatumomab in r/r BL are so far available.  In a retrospective, multi-center, case-series study, these investigators examined 9 patients with r/r BL treated with blinatumomab.  The safety of blinatumomab was evaluated with respect to frequency and severity of AEs -- infections, CRS and neurotoxicity.  PFS, OS and ORR were analyzed to evaluate effectiveness.  No AEs of greater than grade-2 occurred, and AEs were generally treatable and fully reversible.  The best response to blinatumomab was CR in 3/9 patients and PR in 2/9, while 4/9 presented with progressive disease.  Median PFS and OS were 2 and 6 months, respectively, ranging from 5 days to 32 months and 11 days to 32 months, respectively.  The authors concluded that blinatumomab treatment was a successful bridging treatment to hematopoietic stem cell transplantation (HSCT) in 3/9 patients.  The response to blinatumomab varied widely, and only 1 patient survived longer term; however, activity in patients with r/r BL was evident in some patients, with its use being safe, warranting its prospective investigation.  Moreover, these researchers stated that they doubt the use of blinatumomab as a curative monotherapy with long-lasting effects.  Rather they envision blinatumomab as a possible part of combined therapy, especially as a bridging therapy until HSCT in curative intent.  These investigators stated that further investigation should be made in combination with other treatments in the future by collaborative approaches, with the objective of improving the outcomes of patients with r/r Burkitt lymphoma.

Solid Tumors

Ishiguro et al (2017) stated that cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines.  The bi-specific T cell-redirecting antibody (TRAB) is one such promising immunotherapy, which can re-direct T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell.  Because T cells can be re-directed to tumor cells regardless of the specificity of T cell receptors, TRAB is considered effective for less immunogenic tumors lacking enough neoantigens.  Its effectiveness has been exemplified by blinatumomab, a bi-specific T cell engager (TCE) targeting CD19 and CD3, which has shown marked clinical responses against hematological malignancies.  However, the success of TRAB in solid tumors has been hampered by the lack of a target molecule with sufficient tumor selectivity to avoid "on-target off-tumor" toxicity.  Glypican 3 (GPC3) is a highly tumor-specific antigen that is expressed during fetal development; but is strictly suppressed in normal adult tissues.  These researchers developed ERY974, a whole humanized immunoglobulin G-structured TRAB harboring a common light chain, which bi-specifically binds to GPC3 and CD3.  Using a mouse model with reconstituted human immune cells, these investigators showed that ERY974 is highly effective in killing various types of tumors that have GPC3 expression comparable to that in clinical tumors.  ERY974 also induced a robust anti-tumor activity even against tumors with non-immunogenic features, which are difficult to treat by inhibiting immune checkpoints such as PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T lymphocyte-associated protein-4).  Immune monitoring revealed that ERY974 converted the poorly inflamed tumor micro-environment (TME) to a highly inflamed micro-environment.  Toxicology studies in cynomolgus monkeys showed transient cytokine elevation; however, this was manageable and reversible.  No organ toxicity was evident.  The authors concluded that these findings provided a rationale for clinical testing of ERY974 for the treatment of patients with GPC3-positive solid tumors.

Chornoguz et al (2019) noted that although CD3 TRABs have been successfully employed for the treatment of hematological malignancies (blinatumomab), the T-cell signaling pathways induced by these molecules are incompletely understood.  To gain insight into the mechanism of action for TRABs, these researchers created a novel murine CD3xEpCAM bi-specific antibody that incorporates a silent Fc to dissect function and signaling of murine CD8 OT1 T cells upon stimulation.  T-cell-mediated cytotoxicity, cytokine secretion, expression of activation markers, and proliferation were directly induced in T cells treated with the novel CD3xEpCAM bi-specific molecule in-vitro in the presence of epithelial cell adhesion molecule (EpCAM) expressing tumor cells.  Nano-string analysis showed that CD3xEpCAM induced a gene expression profile that resembled antigen-mediated activation, although the magnitude was lower than that of the antigen-induced response.  Furthermore, this CD3xEpCAM bi-specific antibody exhibited in-vivo efficacy.  This was the 1st study that examined both in-vitro as well as in-vivo murine CD8 T-cell function and signaling induced by a CD3xEpCAM antibody having a silent Fc to delineate differences between antigen-independent and antigen-specific T-cell activation.  The authors concluded that these findings enhanced the understanding of T-cell function and signaling induced by CD3 re-direction bi-specific antibodies and may help to develop more effective CD3 re-direction therapeutics for cancer treatment, especially for solid tumors.

Lund et al (2020) stated that glypican-1 is a heparan sulfate proteoglycan that is over-expressed in prostate cancer (PCa), and a variety of solid tumors.  More importantly, expression is restricted in normal tissue, making it an ideal tumor-targeting antigen.  Since there is pre-clinical and clinical evidence of the effectiveness of bi-specific TCE (BiTCE) therapy in PCa, these researchers produced and tested the effectiveness of a GPC-1 targeted BiTCE construct based on the miltuximab sequence.  Miltuximab is a clinical stage anti-GPC-1 antibody that has proven safe in human trials.  The single chain variable fragment (scFv) of miltuximab and the CD3-binding sequence of blinatumomab were combined in a standard BiTCE format.  Binding of the construct to immobilized recombinant CD3 and GPC-1 antigens was assessed by ELISA and BiaCore, and binding to cell surface-expressed antigens was measured by flow cytometry.  The ability of MIL-38-CD3 to activate T cells was assessed using in-vitro co-culture assays with tumor cell lines of varying GPC-1 expression by measurement of CD69 and CD25 expression, before cytolytic activity was assessed in a similar co-culture.  The release of inflammatory cytokines from T cells was measured by ELISA and expression of PD-1 on the T cell surface was measured by flow cytometry.  Binding activity of MIL-38-CD3 to both cell surface-expressed and immobilized recombinant GPC-1 and CD3 was retained.  MIL-38-CD3 was able to mediate the activation of peripheral blood T cells from healthy individuals, resulting in the release of inflammatory cytokines TNF and IFN-g.  Activation was reliant on GPC-1 expression as MIL-38-CD3 mediated only low-level T-cell activation in the presence of C3 cells (constitutively low GPC-1 expression).  Activated T cells were re-directed to lyse PCa cell lines PC3 and DU-145 (GPC-1 moderate or high expression, respectively) but could not kill GPC-1 negative Raji cells.  The expression of PD-1 was up-regulated on the surface of MIL-38-CD3 activated T cells, suggesting potential for synergy with checkpoint inhibition.  The authors concluded that this study reported pre-clinical findings into the effectiveness of targeting GPC-1 in PCa with BiTCE construct MIL-38-CD3.  These researchers showed the specificity and effectiveness of the construct, supporting its further pre-clinical development.

Zhou et al (2021) noted that T-cell-based immunotherapies have revolutionized treatment paradigms in various cancers; however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem.  To address this limitation, strategies for re-directing T cells to treat cancer are being intensively studied, while the BiTCE therapy constitutes one of the most promising therapeutic approaches.  BiTCE is a bi-specific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis.  BiTCE therapy represented by blinatumomab has achieved impressive effectiveness in the treatment of B-cell malignancies; however, major mechanisms of resistance to BiTCE therapy are associated with antigen loss and immunosuppressive factors such as the up-regulation of immune checkpoints.  Therefore, modification of antibody constructs and searching for combination strategies designed to further enhance effectiveness and reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTCE therapy is always poor.  In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies.

Baeuerle and Wesche (2022) stated that T-cell-engaging antibodies or TCEs can connect a patient's cytotoxic T cells with cancer cells, leading to potent re-directed lysis.  Until very recently, only 1 TCE was approved, the CD19/CD3-bispecific blinatumomab.  Many new TCEs in late-stage clinical development target various hematopoietic lineage markers like CD20, BCMA, or CD123.  Although very compelling single-agent activity of TCEs was observed with various blood-borne cancers, therapy of solid tumor indications has thus far been less successful.  The approval in 2022 of the gp100 peptide-major histocompatibility complex (MHC)/CD3 bi-specific TCE tebentafusp in uveal melanoma confirmed that TCEs can also efficiently work against solid tumors.  TCEs targeting peptide-MHC complexes will expand the target space for solid tumor therapy to intra-cellular targets.  Likewise, early clinical trial data from TCEs targeting DLL3 in small cell lung cancer (SCLC) showed promising anti-tumor activity.  Various technologies for conditional activation of TCEs in the TME may expand the scope of conventional surface targets that suffer from a narrow therapeutic window.  Finally, pharmacological enhancements for TCE therapies by engagement of certain co-stimulatory receptors and cytokines, or blockade of checkpoints, are showing promise.  The authors concluded that targeting peptide-MHC complexes, conditional TCE technologies, and concepts enhancing TCE-activated T cells are paving the way towards overcoming challenges associated with solid tumor therapy.

Chen et al (2022) noted that following the approval of the T cell engaging bi-specific antibody blinatumomab, immune cell re-targeting with bi-specific or multi-specific antibodies has emerged as a promising cancer immunotherapy strategy, offering alternative mechanisms compared to immune checkpoint blockade.  As researchers gain better understanding of the complex tumor micro-environment (TEM), rules and design principles have started to take shape on how to best harness the immune system to achieve optimal anti-tumor activities.  These investigators examined the most recent advances and challenges in using bi-specific antibodies for immune cell re-targeting and provided insights into various aspects of antibody engineering.  They discussed studies that highlighted the importance of considering antibody engineering parameters (e.g., binding epitope, affinity, valency, and geometry) to maximize the potency and mitigate the toxicity of TCEs.  Beyond T cell engaging bi-specifics, other bi-specifics designed to recruit the innate immune system were also covered.  The authors concluded that diverse and innovative molecular designs of bi-specific/multi-specific antibodies have the potential to enhance the safety and effectiveness of immune cell re-targeting for the treatment of cancer.  Whether or not clinical data support these different hypotheses, especially in solid tumor settings, remains to be seen.

Wu et al (2023) noted that previous studies have examined the use of engineered blinatumomab-secreting autologous αβ T cells for CD19-targeted cancer therapy.  To create a more flexible allogeneic delivery system, these researchers employed γ9δ2 T cells rather than αβ T cells in a similar application.  First, these investigators showed that γ9δ2 T cells could serve as effector cells for blinatumomab, and these effector memory cells could survive for at least 7 days following infusion.  The genetically modified blinatumomab-secreting γ9δ2 T cells induced significant cytotoxicity in CD19+ tumor cell lines and primary cells from patients with chronic lymphocytic leukemia (CLL).  Of note, blinatumomab-secreting γ9δ2 T cells might also exhibit dual-targeting of CD19 and isopentenyl pyrophosphate, a universal tumor-associated antigen.  In addition, blinatumomab-secreting γ9δ2 T cells killed CD19-transfected adherent cells, suggesting that the γ9δ2 T cells might be effective for treating solid tumors with appropriate cancer antigens.  The authors concluded that these findings suggested that engineered γ9δ2 T cells might exhibit dual-targeting of CD19 and IPP, and the killing mechanism of engineered γ9δ2 T cells could potentially work against cancer cells in solid tumors.  Therefore, these findings support the idea that this platform has high potential for use in other cancers, especially if it is coupled with appropriate bsAbs that target appropriate cancer antigens.  These investigators stated that these findings warrant further studies to advance bsAb-secreting γ9δ2 T cells toward clinical application.

Blinatumomab and Chemotherapy for the Treatment of Infant Acute Lymphoblastic Leukemia

van der Sluis et al (2023) stated that KMT2A-rearranged ALL in infants is an aggressive disease with 3-year event-free survival (EFS) below 40 %.  Most relapses occur during treatment, with 2/3 occurring within 1 year and 90 % within 2 years after diagnosis.  Outcomes have not improved in recent decades despite intensification of chemotherapy.  These researchers examined the safety and effectiveness of blinatumomab in infants with KMT2A-rearranged ALL.  A total of 30 patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 Trial with the addition of 1 post-induction course of blinatumomab (15 μg/square meter of BSA/day; 28-day continuous infusion).  The primary endpoint was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death; MRD was measured by polymerase chain reaction (PCR).  Data on AEs were collected; outcome data were compared with historical control data from the Interfant-06 Trial.  The median follow-up was 26.3 months (range of 3.9 to 48.2).  All 30 patients received the full course of blinatumomab.  No toxic effects meeting the definition of the primary endpoint occurred.  A total of 10 serious AEs were reported (fever [4 events], infection [4 events], hypertension [1 event], and vomiting [1 event]).  The toxic-effects profile was consistent with that reported in older patients.  A total of 28 patients (93 %) either were MRD-negative (16 patients) or had low levels of MRD (less than 5×10-4 [i.e., less than 5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion.  All the patients who continued chemotherapy became MRD-negative during further treatment.  Two-year DFS was 81.6 % in this study (95 % CI: 60.8 to 92.0), as compared with 49.4 % (95 % CI: 42.5 to 56.0) in the Interfant-06 Trial; the corresponding values for OS were 93.3 % (95 % CI: 75.9 to 98.3) and 65.8 % (95 % CI: 58.9 to 71.8).  The authors concluded that blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of effectiveness in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 Trial.

Blinatumomab and CAR T-Cell Therapy in Children with Relapsed/Refractory Leukemia

Wang et al (2023) noted that the 5-year EFS rate for childhood ALL has increased to more than 85 %; however, the 5-year OS rate in children with relapsed/refractory ALL did not exceed 50 %.  In the last 10 years, immunotherapies (such as blinatumomab and chimeric antigen receptor [CAR] T-cell therapy) were approved for relapsed/refractory B-ALL, transforming the treatment environment for children with relapsed/refractory ALL.  In a retrospective, case-series study, these researchers examined how immunotherapy can be incorporated into salvage regimens for pediatric patients with relapsed/refractory ALL by analyzing the diagnosis and treatment process of 7 children with relapsed/refractory leukemia and observing the side effects of the 2 strategies and long-term survival.  The clinical features and treatment responses of patients aged less than 14 years with relapsed/refractory leukemia who received immunotherapy (including CAR T cell therapy and blinatumomab) at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology between February 2014 and April 2022 were analyzed.  A total of 7 children underwent immunotherapy; 5 patients received immunotherapy and sequential allogeneic hematopoietic stem cell transplantation (allo-HSCT), whereas the other 2 received only immunotherapy.  Five patients achieved CR (71.4 %); none of the patients had severe CRS.  However, 1 developed grade-3 immune effector cell-associated neurotoxicity syndrome with prior leukoencephalopathy.  The median follow-up period was 541 days (range of 186 to 3,180 days); no deaths were related to treatment.  Three patients relapsed, 2 had CD19-negative recurrences, and the 3rd showed CD19 antigen reduction.  One patient died after disease progression, whereas the other died of HSCT-related complications.  One patient abandoned the treatment after relapse and was lost to follow-up.  The authors concluded that blinatumomab and CAR T-cell therapy showed excellent remission rates and manageable toxicity in pediatric patients with relapsed/refractory leukemia.  However, the duration of the remission was limited.  Moreover, these researchers stated that further prospective, randomized clinical studies are needed to improve the long-term effectiveness of immunotherapy.

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Appendix

Table: Examples of Tyrosine Kinase Inhibitors (TKIs)

Generic Name	Brand Name
bosutinib	Bosulif
crizotinib	Xalkori
dasatinib	Sprycel
erlotinib	Tarceva
imatinib	Gleevec
lapatinib	Tykerb
nilotinib	Tasigna
sorafenib	Nexavar
sunitinib	Sutent

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References